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Method for synthesizing N-(5-glucose ester valeryl)metoprolol online by lipozyme catalysis

A technology of ester valeryl and vinyl ester valeryl, which is applied in the field of lipase catalyzed on-line controllable and selective synthesis of N-metoprolol, can solve the problems of low bioavailability, short half-life, long reaction time, etc. Effects of reaction time, reduced reaction cost, high conversion and selectivity

Inactive Publication Date: 2017-12-15
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, domestic and foreign studies on the enzymatic synthesis of sugar-containing amine derivatives are more concerned, especially for the synthesis and development of sugar-containing metoprolol compound drugs, improving its pharmacological activity, and solving the half-life of its clinical use. Short, need continuous administration, low bioavailability and other limitations
The reported enzymatic synthesis methods often require a long reaction time (12-24h), and the conversion rate and selectivity of the reaction are not high. Therefore, we found that lipase catalyzed online synthesis of N-(5 -The method of glucosyl valeryl) metoprolol, aims to find a kind of efficient and environment-friendly N-(5-glucosyl valeryl) metoprolol's on-line controllable selective synthesis method

Method used

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  • Method for synthesizing N-(5-glucose ester valeryl)metoprolol online by lipozyme catalysis
  • Method for synthesizing N-(5-glucose ester valeryl)metoprolol online by lipozyme catalysis
  • Method for synthesizing N-(5-glucose ester valeryl)metoprolol online by lipozyme catalysis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Synthesis of N-(5-glucose valeryl)metoprolol

[0029]

[0030] Dissolve N-(5-vinyl valeryl) metoprolol (0.1 mmol) in 0.70 mL DMSO and 9.30 mL tert-amyl alcohol, and dissolve glucose (0.5 mmol) in 0.70 mL DMSO and 9.30 mL tert-amyl alcohol , And then put them in a 10mL syringe for use. 0.87g lipase Lipozyme TL IM is evenly filled in the reaction channel, driven by the PD 1200 syringe pump, the two reaction solutions are respectively 10.4μL·min -1 The flow rate of the reactor enters the reaction channel through the "Y" connector for reaction. The temperature of the reactor is controlled at 35°C through a water bath thermostat. The reaction liquid flows continuously in the reaction channel for 30 minutes. The reaction result is tracked and detected by thin layer chromatography TLC.

[0031] Collect the reaction liquid online through a product collector, distill under reduced pressure to remove the solvent, and pack the column with 200-300 mesh silica gel wet method. ...

Embodiment 2-7

[0036] Change the content of DMSO in the reaction medium (DMSO / tert-amyl alcohol) in the microfluidic channel reactor, and control the temperature to 35°C. Others are the same as in Example 1. The reaction results are shown in Table 1:

[0037] Table 1: The influence of the amount of DMSO in the reaction medium on the reaction

[0038] Example

[0039] The results in Table 1 show that when the flow rate is 10.4μL·min -1 , The reaction time is 30 min, the reaction temperature is 35 ℃, the ratio of the amount of reactant N-(5-vinyl valeryl) metoprolol to glucose is 1:5, and the conversion rate varies with the reaction system (DMSO / Tert-amyl alcohol), the volume ratio of DMSO increases when the amount of DMSO in the mixed solvent of DMSO and tert-amyl alcohol is 7%. Then continue to increase the amount of DMSO in the mixed solvent, which will affect the enzyme Activity affects the conversion rate and selectivity of the reaction. Therefore, the optimal reaction medium in the micro...

Embodiment 8-13

[0041] Change the ratio of the amount of N-(5-vinyl valeryl) metoprolol to the substrate substance of glucose in the microfluidic microchannel reactor and control the temperature at 35°C. Others are the same as in Example 1. The results are shown in Table 2. Show:

[0042] Table 2: The effect of the ratio of the amount of N-(5-vinyl valeryl) metoprolol to glucose substrate on the reaction

[0043]

[0044] The results in Table 2 show that when the flow rate is 10.4μL·min -1 , The reaction time is 30min, the reaction temperature is 35℃, and the DMSO content of the reaction medium is 7%, as the amount of reactant glucose increases, the conversion rate of the reaction also increases, when the ratio of the amount of substrate material is At 1:5, the conversion rate of the reaction is optimal, so the ratio of the amount of the optimal substrate substance in the microfluidic microchannel reactor of the present invention is 1:5.

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Abstract

The invention discloses a method for synthesizing N-(5-glucose ester valeryl)metoprolol online by lipozyme catalysis. The method takes N-(5-vinyl ester valeryl)metoprolol and glucose as raw materials according to the amount of substance ratio of 1 to (1 to 10), dimethyl sulfoxide and tert-amyl alcohol as reaction solvents and lipozyme TL IM as a catalyst, and comprises the following steps: putting the raw materials and the reaction solvents into an injector; uniformly filling the lipozyme TL IM into a reaction channel of a micro-fluidic channel reactor; continuously introducing the raw materials and the reaction solvents into a reaction channel device under the pushing of the injector and carrying out ester exchange reaction, wherein the inner diameter of the reaction channel of the micro-fluidic channel reactor is 0.8mm to 2.4mm and the length of the reaction channel is 0.5m to 1.0m; controlling the esterification reaction temperature to 20 DEG C to 60 DEG C and the esterification reaction time to 20min to 40min; collecting a reaction solution online through a product collector and carrying out conventional post-treatment on the reaction solution to obtain the N-(5-glucose ester valeryl)metoprolol. The method disclosed by the invention has the advantages of short reaction time, high selectivity and high yield.

Description

(1) Technical field [0001] The invention relates to a method for lipase-catalyzed online controllable and selective synthesis of N-(5-glucose valeryl) metoprolol. (2) Background technology [0002] At present, the most commonly used drugs in clinical practice are small-molecule drugs, but small-molecule drugs have fast metabolism, short half-life and obvious peak-to-valley effects, resulting in frequent administration. Small-molecule drugs are prepared by chemical and biological methods to prepare new drug derivatives Or sugar-containing drug derivatives and polymer prodrugs of drugs are an effective method to improve the sustained release and targeting of drugs. [0003] At this stage, most drugs face the problem of too high fat solubility or poor water solubility, and the existence of these problems leads to poor gastrointestinal absorption of the drug and poor oral bioavailability. To this end, researchers have improved the water solubility and oral bioavailability of the drug ...

Claims

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Application Information

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IPC IPC(8): C12P19/26C12P19/02
CPCC12P19/02C12P19/26
Inventor 杜理华周娜妮蒋志鹏罗锡平
Owner ZHEJIANG UNIV OF TECH
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